Recent FDA approval of HIV protease inhibitors in combination with reverse transcriptase inhibitors has marked a new era of AIDS chemotherapy. Despite these important advances, a number of major limitations have emerged: (i) the presence of a substantial "peptide-like" character in his protease inhibitors; (ii) higher therapeutic doses and inability to cross the blood-brain barrier; (iii) inadequate supply and expensive synthesis; (iv) the tendency of the virus to become resistant to drugs. The research plan involves the design and synthesis of non-peptidal protease inhibitors with improve resistance profiles. The specific aims of the proposal are: (a) to design and synthesize novel functionalities that replace peptide binding but mimic the biological model of action based upon X-ray crystal structures of the protein-ligand complexes; (b) to further optimize the lead structures based upon molecular modeling and to further optimize the lead structures based upon molecular modeling and structure-based design strategies to combat drug resistance; (c) to demonstrate the utility of such molecular design through the synthesis of small molecule (550 daltons) non-peptidal HIV protease inhibitors (with subnanomolar potency).